Skip to main content

Advertisement

SpringerLink
Log in

Potentiation of triclabendazole sulphoxide-induced tegumental disruption by methimazole in a triclabendazole-resistant isolate of Fasciola hepatica

  • Original Paper
  • Published:
Parasitology Research Aims and scope Submit manuscript

Abstract

A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of drug metabolism. The flavin monooxygenase system (FMO) was inhibited using methimazole (MTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The FMO system was inhibited by a 2-h pre-incubation in methimazole (100 μM), then incubated for a further 22 h in NCTC medium containing either MTZ; MTZ+nicotinamide adenine dinucleotide phosphate (NADPH) (1 nM); MTZ+NADPH+TCBZ (15 μg/ml); or MTZ+NADPH+triclabendazole sulphoxide (TCBZ.SO) (15 μg/ml). Changes to fluke ultrastructure following drug treatment and metabolic inhibition were assessed using transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than triclabedazole-resistant isolate. However, co-incubation with MTZ+TCBZ, but more particularly MTZ+TCBZ.SO, led to more severe changes to the TCBZ-resistant isolate than with each drug on its own, with severe swelling of the basal infolds and mucopolysaccharide masses in the syncytium, accompanied by a reduction in numbers of secretory bodies. The synthesis and production of secretory bodies in the tegumental cells was severely affected as well. With the TCBZ-susceptible Cullompton isolate, there was limited potentiation of drug action. The results support the concept of altered drug metabolism in TCBZ-resistant flukes, and this process may play a role in the development of drug resistance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Figs. 1–5 1 2 3 4 5
Figs. 6–11 6 7 8 9 10 11
Figs. 12–16 12 13 14 15 16
Figs. 17–20 17 18 19 20
Figs. 21–26 21 22 23 24 25 26

Similar content being viewed by others

References

  • Alvarez LI, Solana HD, Mottier ML, Virkel GL, Fairweather I, Lanusse CE (2005) Altered drug influx/efflux and enhanced metabolic activity in triclabendazole-resistant liver flukes. Parasitology 131:501–510

    Article  CAS  PubMed  Google Scholar 

  • Anderson HR, Fairweather I (1995) Fasciola hepatica: ultrastructural changes to the tegument of juvenile flukes following incubation in vitro with the deacetylated (amine) metabolite of diamphenethide. Int J Parasitol 25:319–333

    Article  CAS  PubMed  Google Scholar 

  • Buchanan JF, Fairweather I, Brennan GP, Trudgett A, Hoey EM (2003) Surface and internal tegumental changes induced by treatment in vitro with the sulphoxide metabolite of albendazole (“Valbazen”). Parasitology 126:141–153

    Article  CAS  PubMed  Google Scholar 

  • Devine C, Brennan GP, Lanusse CE, Alvarez LI, Trudgett A, Hoey E, Fairweather I (2009) Effect of the metabolic inhibitor, methimazole on the drug susceptibility of a triclabendazole-resistant isolate of Fasciola hepatica. Parasitology 136:183–192

    Article  CAS  PubMed  Google Scholar 

  • Devine C, Brennan GP, Lanusse CE, Alvarez LI, Trudgett A, Hoey E, Fairweather I (2010) Inhibition of cytochrome P450-mediated metabolism enhances ex vivo susceptibility of Fasciola hepatica to triclabendazole. Parasitology (in press)

  • Fairweather I (2005) Triclabendazole: new skills to unravel an old(ish) enigma. J Helminthol 79:227–234

    Article  CAS  PubMed  Google Scholar 

  • Fairweather I (2009) Triclabendazole progress report, 2005–2009: an advancement of learning? J Helminthol 83:139–150

    Article  CAS  PubMed  Google Scholar 

  • Fairweather I, Anderson HR, Threadgold LT (1986) Fasciola hepatica: tegumental changes induced in vitro by the deacetylated (amine) metabolite of diamphenethide. Exp Parasitol 62:336–348

    Article  CAS  PubMed  Google Scholar 

  • Fairweather I, Threadgold LT, Hanna REB (1999) Development of Fasciola hepatica in the mammalian host. In: Dalton JP (ed) Fasciolosis. CAB International, Wallingford, pp 47–111

    Google Scholar 

  • González Canga A, Sahagún Prieto AM, Diez Liébana MJ, Fernández Martínez N, Sierra Vega M, GarcíaVieitez JJ (2009) The pharmacokinetics and metabolism of ivermectin in domestic animal species. Vet J 179:25–37

    Article  PubMed  Google Scholar 

  • Halferty L, Brennan GP, Hanna REB, Edgar HW, Meaney MM, McConville M, Trudgett A, Hoey L, Fairweather I (2008) Tegumental surface changes in juvenile Fasciola hepatica in response to treatment in vivo with triclabendazole. Vet Parasitol 155:49–58

    Article  CAS  PubMed  Google Scholar 

  • Halferty L, Brennan GP, Trudgett A, Hoey L, Fairweather I (2009a) The relative activity of triclabendazole metabolites against the liver fluke, Fasciola hepatica. Vet Parasitol 159:126–138

    Article  CAS  Google Scholar 

  • Halferty L, O’Neill JF, Brennan GP, Keiser J, Fairweather I (2009b) Electron microscopical study to assess the in vitro effects of the synthetic trioxolane OZ78 against the liver fluke, Fasciola hepatica. Parasitology 136:1325–1337

    Article  CAS  Google Scholar 

  • Hennessy DR, Lacey E, Steel JW, Prichard RK (1987) The kinetics of triclabendazole disposition in sheep. J Vet Pharmacol Ther 10:64–72

    Article  CAS  PubMed  Google Scholar 

  • Keiser J, Utzinger J, Vennerstrom JL, Dong Y, Brennan GP, Fairweather I (2007) Activity of artemether and OZ78 against triclabendazole-resistant Fasciola hepatica. Trans R Soc Trop Med Hyg 101:1219–1222

    Article  CAS  PubMed  Google Scholar 

  • Lanusse CE, Prichard RK (1992a) Effects of methimazole on the kinetics of netobimin metabolites in cattle. Xenobiotica 22:115–123

    Article  CAS  Google Scholar 

  • Lanusse CE, Prichard RK (1992b) Methimazole increases the plasma concentrations of the albendazole metabolites of netobimin in sheep. Biopharm Drug Dispo 13:95–103

    Article  CAS  Google Scholar 

  • Lanusse CE, Prichard RK (1993) Clinical pharmacokinetics and metabolism of benzimidazole anthelmintics in ruminants. Drug Metab Rev 25:235–279

    Article  CAS  PubMed  Google Scholar 

  • Lanusse CE, Gascon L, Prichard RK (1992) Methimazole-mediated modulation of netobimin biotransformation in sheep: a pharmacokinetic assessment. J Vet Pharmacol Ther 15:267–274

    Article  CAS  PubMed  Google Scholar 

  • Lanusse CE, Gascon LH, Prichard RK (1995) Influence of the antithyroid compound methimazole on the plasma disposition of fenbendazole and oxfendazole in sheep. Res Vet Sci 58:222–226

    Article  CAS  PubMed  Google Scholar 

  • McConville M, Brennan GP, McCoy M, Castillo R, Hernández-Campos A, Ibarra F, Fairweather I (2006) Adult triclabendazole-resistant Fasciola hepatica: surface and subsurface tegumental responses to in vitro treatment with the sulphoxide metabolite of the experimental fasciolicide compound alpha. Parasitology 133:195–208

    Article  CAS  PubMed  Google Scholar 

  • McConville M, Brennan GP, McCoy M, Castillo R, Hernández-Campos A, Ibarra F, Fairweather I (2007) Immature triclabendazole-resistant Fasciola hepatica: tegumental responses to in vitro treatment with the sulphoxide metabolite of the experimental fasciolicide compound alpha. Parasitol Res 100:365–377

    Article  CAS  PubMed  Google Scholar 

  • McConville M, Brennan GP, Flanagan A, Edgar HWJ, McCoy M, Castillo R, Hernández-Campos A, Fairweather I (2008) Surface and internal tegumental changes in juvenile Fasciola hepatica following treatment in vivo with the experimental fasciolicide, compound alpha. Vet Parasitol 153:52–64

    Article  CAS  PubMed  Google Scholar 

  • McConville M, Brennan GP, Flanagan A, Edgar HWJ, Hanna REB, McCoy M, Gordon AW, Castillo R, Hernández-Campos A, Fairweather I (2009a) An evaluation of the efficacy of compound alpha and triclabendazole against two isolates of Fasciola hepatica. Vet Parasitol 162:75–88

    Article  CAS  Google Scholar 

  • McConville M, Brennan GP, Flanagan A, Edgar HWJ, Castillo R, Hernández-Campos A, Fairweather I (2009b) Ultrastructural changes to the tegumental system and the gastrodermal cells in adult Fasciola hepatica following in vivo treatment with the experimental fasciolicide, compound alpha. Parasitology 136:665–680

    Article  CAS  Google Scholar 

  • McCoy MA, Fairweather I, Brennan GP, Kenny JM, Forbes AF (2005) The efficacy of nitroxynil and triclabendazole administered synchronously against juvenile triclabendazole-resistant Fasciola hepatica in sheep. Res Vet Sci 78(suppl A):33

    Google Scholar 

  • McKinstry BD (2008) Ultrastructural changes observed in Fasciola hepatica following treatment with nitroxynil and triclabendazole, alone and in combination. PhD Thesis, The Queen’s University of Belfast

  • McKinstry B, Brennan GP, Halferty L, Forbes AB, Fairweather I (2007) Ultrastructural changes induced in the tegument and gut of Fasciola hepatica following in vivo and in vitro drug treatment with nitroxynil (Trodax). Parasitol Res 101:929–941

    Article  CAS  PubMed  Google Scholar 

  • McKinstry B, Halferty L, Brennan GP, Fairweather I (2009) Morphological response of triclabendazole-resistant isolates of Fasciola hepatica to treatment in vitro with nitroxynil (Trodax). Parasitol Res 104:645–655

    Article  CAS  PubMed  Google Scholar 

  • Meaney M, Fairweather I, Brennan GP, Forbes AB (2004) Transmission electron microscope study of the ultrastructural changes induced in the tegument and gut of Fasciola hepatica following treatment with clorsulon. Parasitol Res 92:232–241

    Article  CAS  PubMed  Google Scholar 

  • Meaney M, Haughey S, Brennan GP, Fairweather I (2005) Ultrastructural observations on oral ingestion and trans-tegumental uptake of clorsulon by the liver fluke, Fasciola hepatica. Parasitol Res 95:201–212

    Article  CAS  PubMed  Google Scholar 

  • Meaney M, Allister J, McKinstry B, McLaughlin K, Brennan GP, Forbes AB, Fairweather I (2006) Fasciola hepatica: morphological effects of a combination of triclabendazole and clorsulon against mature fluke. Parasitol Res 99:609–621

    Article  CAS  PubMed  Google Scholar 

  • Meaney M, Allister J, McKinstry B, McLauglin K, Brennan GP, Forbes AB, Fairweather I (2007) Fasciola hepatica: ultrastructural effects of a combination of triclabendazole and clorsulon against mature fluke. Parasitol Res 100:1091–1104

    Article  CAS  PubMed  Google Scholar 

  • Mottier L, Virkel G, Solana H, Alvarez L, Salles J, Lanusse C (2004) Triclabendazole biotransformation and comparative diffusion of the parent drug and its oxidized metabolites into Fasciola hepatica. Xenobiotica 34:1043–1047

    Article  CAS  PubMed  Google Scholar 

  • Mottier L, Alvarez L, Ceballos L, Lanusse C (2006) Drug transport mechanisms in helminth parasites: passive diffusion of benzimidazole anthelmintics. Exp Parasitol 113:49–57

    Article  CAS  PubMed  Google Scholar 

  • O’Neill JF, Johnston RC, Halferty L, Brennan GP, Keiser J, Fairweather I (2009) Adult triclabendazole-resistant Fasciola hepatica: morphological responses to in vivo treatment with artemether in the rat model. J Helminthol 83:151–163

    Article  PubMed  Google Scholar 

  • Robinson MW, Trudgett A, Hoey EM, Fairweather I (2002) Triclabendazole-resistant Fasciola hepatica: β-tubulin and response to in vitro treatment with triclabendazole. Parasitology 124:325–338

    Article  CAS  PubMed  Google Scholar 

  • Robinson MW, Lawson J, Trudgett A, Hoey EM, Fairweather I (2004) The comparative metabolism of triclabendazole sulphoxide by triclabendazole-susceptible and triclabendazole-resistant Fasciola hepatica. Parasitol Res 92:205–210

    Article  PubMed  Google Scholar 

  • Rogan MT, Threadgold LT (1984) Fasciola hepatica: tegumental changes as a result of lectin binding. Exp Parasitol 57:248–260

    Article  CAS  PubMed  Google Scholar 

  • Skuce PJ, Fairweather I (1990) The effect of the hydrogen ionopore closantel upon the pharmacology and ultrastructure of the adult fluke Fasciola hepatica. Parasitol Res 76:241–250

    Article  CAS  PubMed  Google Scholar 

  • Skuce PJ, Anderson HR, Fairweather I (1987) The interaction between the deacetylated (amine) metabolite of diamphenethide (DAMD) and cytochemically demonstrable Na+/K+-ATPase activity in the tegument of Fasciola hepatica. Parasitol Res 74:161–167

    Article  CAS  PubMed  Google Scholar 

  • Stitt A, Fairweather I (1994) The effect of the sulphoxide metabolite of triclabendazole (‘Fasinex’) on the tegument of mature and immature stages of the liver fluke, Fasciola hepatica. Parasitology 108:555–567

    Article  CAS  PubMed  Google Scholar 

  • Threadgold LT, Brennan GP (1978) Fasciola hepatica: basal infolds and associated vacuoles of the tegument. Exp Parasitol 46:300–316

    Article  CAS  PubMed  Google Scholar 

  • Toner E, McConvery F, Brennan GP, Meaney M, Fairweather I (2009) A scanning electron microscope study on the route of entry of triclabendazole into the liver fluke, Fasciola hepatica. Parasitology 136:523–535

    Article  CAS  PubMed  Google Scholar 

  • Toner E, Brennan GP, McConvery F, Meaney M, Fairweather I (2010) A transmission electron microscope study on the route of entry of triclabendazole into the liver fluke, Fasciola hepatica. Parasitology (in press)

  • Virkel G, Lifschitz A, Sallovitz J, Pis A, Lanusse C (2006) Assessment of the main metabolism pathways for the flukicidal compound triclabendazole in sheep. J Vet Pharmacol Ther 29:213–223

    Article  CAS  PubMed  Google Scholar 

  • Virkel G, Lifschitz A, Sallovitz J, Ballent M, Scarcella S, Lanusse C (2009) Inhibition of cytochrome P450 activity enhances the systemic availability of triclabendazole metabolites in sheep. J Vet Pharmacol Ther 32:79–86

    Article  CAS  PubMed  Google Scholar 

  • Walker SM, McKinstry B, Boray JC, Brennan GP, Trudgett A, Hoey EM, Fletcher H, Fairweather I (2004) Response of two isolates of Fasciola hepatica to treatment with triclabendazole in vivo and in vitro. Parasitol Res 94:427–438

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This investigation was supported by a DARDNI Postgraduate Studentship to Catherine Devine. It was also partially supported by a grant from the European Union (DELIVER grant, no. FOOD-CT-200X-023025) and by a BBSRC/Defra grant (C00082X/1).

Author information

Authors and Affiliations

  1. Parasite Therapeutics Group, School of Biological Sciences, Medical Biology Centre, The Queen’s University of Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK

    Catherine Devine, Gerard P. Brennan, Alan Trudgett, Elizabeth Hoey & Ian Fairweather

  2. Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario (UNCPBA), 7000, Tandil, Argentina

    Carlos E. Lanusse & Luis I. Alvarez

Authors
  1. Catherine Devine
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gerard P. Brennan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carlos E. Lanusse
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luis I. Alvarez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alan Trudgett
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elizabeth Hoey
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ian Fairweather
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ian Fairweather.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Devine, C., Brennan, G.P., Lanusse, C.E. et al. Potentiation of triclabendazole sulphoxide-induced tegumental disruption by methimazole in a triclabendazole-resistant isolate of Fasciola hepatica . Parasitol Res 106, 1351–1363 (2010). https://doi.org/10.1007/s00436-010-1806-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00436-010-1806-1

Keywords

Search

Navigation